PROJECT SUMMARY/ABSTRACT Cancer is the second leading cause of death in women of reproductive age. Pregnancy-associated cancers (diagnosed during pregnancy or up to 5 years postpartum) are increasing, highly lethal, and particularly devastating because they occur in young mothers. Breast cancer is known to have higher incidence and mortality in women who have recently given birth compared with other young women. However, little is known about pregnancy-associated cancers at sites other than the breast, such as the ovary, colon/rectum, and melanoma of the skin, which are relatively common and lethal, yet rarely have been examined. Limited evidence suggests that ovarian, colorectal, and melanoma cancers may have higher incidence and poorer outcomes in pregnant or postpartum women than in other young women. The underlying mechanisms may involve pro-angiogenic factors required for embryonic implantation (e.g., vascular endothelial growth factor [VEGF]), immunosuppression to avoid fetal rejection, and high levels of hormones required for fetal growth (e.g., insulin-like growth [IGF] factors, estrogens, and pregnancy-associated plasma protein-A [PAPPA]). We hypothesize that due to the pro-carcinogenic effects of angiogenic, immunosuppressive, and growth factors, pregnancy and the postpartum period are associated with higher incidence and mortality of ovarian, colorectal, and melanoma cancers. We will test these hypotheses by conducting the largest and most comprehensive population-based cohort studies to date of incidence patterns, diagnostic characteristics, and mortality of these cancers in pregnant and postpartum women using data for the entire population of Sweden, including all ~3.0 million women of reproductive age (15 to 49 years) during 1973-2014. Sweden is the ideal setting for the proposed study because of the availability of nearly 100% complete birth, cancer, and death registry data for the entire population, affording the large sample sizes needed to examine pregnancy-associated cancers with good statistical power. Cancer incidence and mortality rates are similar in Sweden and the US, and have the same major underlying biologic mechanisms. Our specific aims are to: (1) determine the incidence, diagnostic characteristics, histologic subtypes, and time windows of susceptibility for pregnancy-associated ovarian, colorectal, and melanoma cancers; and (2) determine mortality for these pregnancy-associated cancers and their most common subtypes. The proposed research is significant and innovative because it will be the largest and most comprehensive studies to date to identify the incidence, diagnostic characteristics, and mortality of pregnancy-associated cancers. It will have high statistical power to determine whether or not pregnancy is associated with increases in ovarian, colorectal, and melanoma cancers, and poorer outcomes in this understudied population of young mothers, as we hypothesize. The results will advance our understanding of pregnancy-associated cancers, inform clinical management and counseling, and guide future studies of other cancer sites and preventive or therapeutic interventions to reduce cancer incidence and mortality in women.